Considerable public attention has focused recently on the question of why there has been a rather dramatic upsurge recently in the rate at which the diagnosis of bipolar disorder (BD) is being assigned to children. In large part the upsurge appears to be due to the fact that children with extremely severe irritability, but without distinct manic episodes, are receiving the diagnosis of BD. At the inception of this project, we defined criteria that would allow us to identify reliably children in this controversial diagnostic group. We called the syndrome severe mood and behavioral dysregulation (SMD), and defined it in terms of impairing symptoms that include abnormal baseline mood (i.e. irritability, anger, and/or sadness), hyperarousal (e.g. insomnia, agitation, distractibility), and increased reactivity to negative emotional stimuli. The specific goals of this project are 1) to identify reliably a group of children with severe mood and behavioral dysregulation in order to characterize them clinically and behaviorally, and follow them longitudinally, 2) to compare the brain function of SMD children (assessed with functional MRI and standardized behvioral testing) to that of children with unequivocal BPD; 3) to test appropriate treatments for SMD. The latter is particularly important, since if youth with SMD are found to have a form of BD that would dictate one course of treatment, whereas if they are found to have (for example) a variant of depression, anxiety, and/or attention deficit hyperactivity disorder, this would dictate a rather different plan for treatment.[unreadable] Since the inception of this project, approximately 200 youth have been recruited into the project, approximately 100 of whom are patients with SMD. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. In past years, we demonstrated that youth with SMD are at risk for major depression, rather than necessarily BD, in early adulthood, and that they are less likely than youth with BD to have a parent with BD. These data would suggest that youth with SMD should not be considered to be suffering from a form of BD. On the other hand, youth with SMD and BD differ from youth with depression, attention deficit hyperactivity disorder (ADHD), or anxiety in that only those with BD or SMD have deficits in face emotion identification. This year we completed neuroimaging studies comparing these different populations in terms of neural activation while viewing faces and rating the emotion on the face and their own response to the face. We found that youth with BD and those with SMD differed in amygdala activation while viewing such faces. We also finished a study comparing brain activation in these groups while the subjects perform a task requiring motor inhibition or response flexibility. These data are being analyzed.[unreadable] Finally this year we completed a double-blind placebo-controlled study of lithium, with accompanying magnetic resonance spectroscopy (MRS). The results of this study indicate that lithium did not provide more clinical benefit than placebo, nor were effects on brain chemistry discerned with MRS. A new treatment trial, using different pharmacologic agents, has been submitted for approval.